Abnormal regulation of hepatic glucocorticoid receptor mRNA and receptor protein distribution in the obese Zucker rat.

This study examines the cellular distribution of glucocorticoid receptor (GR) protein and transcriptional activity of the GR gene in the liver of Zucker obese (fa/fa) rats. Immunoabsorption and Western blotting showed an increase in nuclear GR protein level but a decrease in cytosolic GR levels in the liver of 5-week old male obese rats (fa/fa) compared to their lean littermates (Fa/-). These changes were confirmed by receptor-ligand binding assays with [3H]-dexamethasone which showed a sixfold increase in average obese nuclear GR binding and a twofold reduction in cytosolic GR binding. HSP90, but not HSP70, levels were reduced in hepatic cytosol and increased in hepatic nuclei prepared from obese rats. Using Northern blot analysis of hepatic RNA, we demonstrated a twofold increase in hepatic mRNAs for GR, malic enzyme (ME), tyrosine aminotransferase (TAT), and glyceraldehyde 3-PO4-dehydrogenase in the obese rat. Increased transcription of GR and ME mRNAs in obese nuclei was indicated in nuclear run-on assays. These data suggest that there is increased nuclear localization of GR in the liver of obese rats and suggests that increased transcription of GR gene may contribute to this effect. The described changes may contribute to the abnormal regulation by glucocorticoids of some hepatic genes in the Zucker fa/fa rat.